A subchondral defect is usually characterized by a structural breakdown of the articular cartilage and the bone underneath due to trauma or disease, leading to chronic disabilities. Treating such defects is an important regenerative medicine target since damaged cartilage cannot spontaneously heal itself in adults. The avascular cartilage with its dense extracellular matrix prevents chondro-progenitors from migrating to the injury site, thus greatly reducing the tissue's regenerative potential. For decades, cell-based strategies have been developed for treating cartilage defects, by injecting cell suspensions (chondrocytes, stem cells) or their combination with biomaterials (Marcacci M. et al., 2005, Crawford D C. et al., 2009). These strategies have encountered crucial barriers in therapeutic translation, due to concerns with the cells in use (e.g., rejection, pathogen contaminants, tumorigenesis) and technical issues (packaging, storage, shipping) as well as difficulties in clinical adoption and regulatory approval (Prockop D J. et al., 2009).
Nowadays, following the identification and efficient production of molecular inducers of tissue regeneration and with the development of hydrogels for their sustained delivery, there is a shift in trend towards adopting acellular therapeutic approaches. Such strategies have been fueled by the finding that micro-fracture surgical techniques can induce the recruitment of bone marrow stem cells into the chondral defect and initiate its repair. To enhance endogenous cell recruitment, combinations of molecular inducers and biomaterials to prolong factor activity, have been applied (Nixon A J, et al., 1999, Gotterbarm T. et al., 2006). These strategies for repairing osteochondral defects are still in their infancy and are considered to be provocative, and in need of additional testing (Laird D J. et al., 2008, Karp J M. et al., 2009).
WO 2007/043050, one inventor of which is a co-inventor of the present invention, provides bioconjugates comprising a sulfated polysaccharide such as alginate sulfate and hyaluronan sulfate and at least one bioactive polypeptide capable of binding a sulfate group of said sulfated polysaccharide. The bioactive polypeptide can be a heparin-binding polypeptide or a positively-charged polypeptide and is preferably a peptide growth factor or a cytokine. The bioconjugates serve as delivery systems for sustained release of the bioactive polypeptides.
Affinity binding of TGF-β1 to alginate-sulfate/alginate scaffold was recently disclosed (Re'em et al., 2012), demonstrating that such binding maintained the factor's activity, enabled its sustained release and promoted human mesenchymal stem cell differentiation towards committed chondrocyte.